1. Field of the Invention
The present invention relates to a pharmaceutical composition for the therapy of sepsis or septic shock comprising a Smad6-derived peptide as an active ingredient, and a method for treating sepsis or septic shock using the same.
2. Description of the Related Art
Sepsis is a systemic inflammatory response syndrome that occurs in response to a pathogenic process in which, when Gram-negative bacteria infect the body, the toxin lipopolysaccharide (LPS), a cell wall constituent, excessively activates the immune system, with a side effect in severe cases of causing the body to go into shock. Sepsis is a serious disease, and a major cause of death among patients hospitalized with serious illnesses, with a mortality rate of 30%. In spite of great advances in medical technology, sepsis is often caused by infections which occur following surgical operations, and this happens all around the world. In addition, bacterial infection in people with weak immune systems, such as infants and the elderly, may be especially liable to develop sepsis. For example, neonatal sepsis is known to affect 3 in 1,000 mature infants, with a 3- to 4-fold increase in attack rate for immature infants. Upon the onset of sepsis, the treatment thereof generally rests on antibiotics. If bacteria grow too excessively due to the absence of proper treatment, or if bacteria are highly resistant to antibiotics, the sepsis cannot be effectively treated with antibiotics alone.
Like this, with the increasing advent of pathogens resistant to antibiotics, the treatment thereof has emerged as a very important and pressing task, but proper therapeutics have not yet been developed thus far (Weikert, L F Clin., Chest Med., 17, pp 289-305, 1996).
TGF-β (Transforming growth factor-β) is a cytokine that controls various physiological processes including cell growth, cell differentiation, apoptosis, cell migration, the production of extracellular matrix (ECM), vascularization, and embryogenesis in the body. The mature TGF-β protein dimerizes to produce a 25 KDa active molecule. TGF-β signaling begins with the binding of secreted, active TGF-β to a serine/threonine receptor kinase on the cell membrane. There are two classes of TGF-β receptors: type I and type II. The TGF-β binds to a constitutively active, type II receptor dimer, which phosphorylates and recruits a type I receptor dimer, forming a heterotetrameric complex with the ligand. In the TGF-β signaling pathway, Smad act as a transcription factor which transduces extracellular signals from TGF-β to the nucleus. When phosphorylated by a type II receptor, the type I receptor phosphorylates and activates Smad proteins, which, in turn, accumulate in the nucleus wherein they act in cooperation with other transcription factors to participate in the regulation of downstream gene expression (Masague J, Seoane J, Wotton D. Genes Dev 19:2783-2810, 2005).
In response to TGF-β, cells exhibit various activities which vary depending on the type of cells or the situation of stimuli, such as stimulated or inhibited growth, apoptosis, differentiation, etc. For example, TGF-β stimulates epithelial cells to actively proliferate, causing oncogenesis (Siegel P M, Massague J. Nat Rev Cancer 3: 807-821, 2003). Cytokines in the TGF-β family bind to various type I and type II receptors. Up to date, there are seven known type I receptors, called ALK (activin receptor-like kinase), and five type II receptors. TGF-β ligands utilize ALK5 and TR-2 receptors in most cells.
There are eight known Smad proteins, which can be divided into three classes: Receptor-activated Smads (R-Smad) which include Smad1, Smad2, Smad3, Smad5, and Smad8; Common mediator Smad (Co-Smad which includes only Smad4; and Inhibitory Smads (I-Smad) which include Smad6 and Smad7. On the whole, the TGF-β/Activin/Nodal group is mediated by Smad2 and Smad3 while the BMP/GDF/MIS group takes advantage of Smad1, Smad5, and Smad8 in the R-Smad. When bound to a ligand, the type I receptors directly phosphorylate the SSXS motif in the carboxyl tail of R-Smad, and the phosphorylated R-Smad, in turn, interacts with the Co-Smad, Smad4 and translocates into the nucleus where they bind to the Smad-binding element (SBE) on the DNA (Shi Y, Wang Y F, Jayaraman L, Yang H, Massague J, Pavletich N P. Cell 94: 585-594, 1998). Often, SBE acts as a binding site for other transcription factors so that the Smad regulates gene expression in cooperation with the other transcription factors. In contrast to R-Smad and Co-Smad, I-Smads (Smad6 and Samd7) have no carboxyl termini which can be phosphorylated by type I receptors, and downregulates the TGF-signaling. One of the most well known responses of cells to TGF-β is growth arrest. TGF-β induces cell growth arrest in epithelial cells, endothelial cells, blood cells, and nerve cells. Stimulation of TGF-β transduces the signals at any phase of the cell cycle, and also induces G1 arrest in the cell cycle (Massague J, Gomis R R. FEES Lett 580: 2811-2820, 2006). In epithelial cells, TGF-β stimulation induces the transcription of cyclin-dependent kinase inhibitors such as p21Cip1/WAF1 and p15lnk4b to activate anti-proliferative reactions, which leads to G1 arrest in the cell cycle. In addition, TGF-β inhibits the transcription of the pro-growth transcription factor c-Myc and the differentiation inhibitors ld1, ld2, and ld3. Also, TGF-β is known to induce various apoptotic reactions.
As reviewed above, TGF-β ligands and their signaling mediators, Smads, are not only involved in physiological activities such as cell growth, embryogenesis, and differentiation, but also play an important role in oncogenesis, fibrosis, and the onset and progression of various diseases. Factors and systems capable of controlling the signaling pathway, and detection methods thereof are now being actively studied.
However, any therapeutic effects that Smad6 in the TGF-β signaling pathway may have on sepsis or septic shock have yet to be discovered.